The mammalian immune response is mediated by several types of cells that interact specifically with foreign material, i.e., antigens. One of these cell types, B cells, is responsible for the production of antibodies. Another cell type, T cells, include a wide variety of cellular subsets that destroy cells infected with virus or control the in vivo function of both B cells and other hematopoietic cells, including T cells. A third cell type, macrophages, process and present antigens in conjunction with major histocompatibility complex (MHC) proteins to T cells. Communication between these cell types is mediated in a complex manner by lymphokines, such as interleukins 1–6 and γ-IFN (see, generally, Paul, W. E., ed., Fundamental Immunology, 3rd ed., Raven Press, New York (1993), which is incorporated herein in relevant part by reference.)
One important lymphokine is γ-IFN, which is secreted by some T cells. In addition to its anti-viral activity, γ-IFN stimulates natural killer (NK) cells and T helper 1 (Th1) cells, activates macrophages, and stimulates the expression of MHC molecules on the surface of cells (Paul, op. cit., pp. 764–766). Hence γ-IFN generally serves to enhance many aspects of immune function, and is a logical candidate for a therapeutic drug in cases where such enhancement is desired, e.g., in treating cancer. Conversely, in disease states where the immune system is over-active, e.g., autoimmune diseases and organ transplant rejection, antagonists of γ-IFN can be useful to treat the disease by neutralizing the stimulatory effects of γ-IFN.
Mouse monoclonal antibodies that bind to and neutralize γ-IFN have been reported (see, e.g., Van der Meide et al., J. Gen. Virol, 67, 1059 (1986)). Such anti-γ-IFN antibodies have been reported to delay or prevent rejection in vitro and in vivo mouse models of transplants, (Landolfo et al., Science 229, 176 (1985) and Rosenberg et al., J. Immunol. 144, 4648 (1990)), both of which are incorporated herein by reference). Treatment of mice prone to develop a syndrome like systemic lupus erythematosus (SLE) with a monoclonal antibody to γ-IFN was reported to delay onset of the disease (Jacob et al., J. Exp. Med. 166, 798 (1987)). An anti-γ-IFN antibody has also been reported to alleviate adjuvant arthritis in rats (Jacob et al., J. Immunol. 142, 1500 (1989))and colitis in mice. (Powrie et al., Immunity 1, 553–562 (1994)). Queen et al., WO 92/11018 discuss the mouse AF2 antibody to γ-IFN, certain humanized immunoglobulins, and use of the same for treating inflammatory disease.
The use of non-human monoclonal antibodies such as AF2 has certain drawbacks in human treatment, particularly in repeated therapeutic regimens as explained below. Mouse monoclonal antibodies, for example, have a relatively short circulating half-life in humans, and lack other important immunoglobulin functional characteristics when used in humans.
Perhaps more importantly, murine monoclonal antibodies contain substantial amino acid sequences that will be immunogenic when injected into a human patient. Numerous studies have shown that, after injection of a foreign antibody, the immune response elicited by a patient against the injected antibody can be quite strong, essentially eliminating the antibody's therapeutic utility after an initial treatment. Moreover, if mouse or other antigenic (to humans) monoclonal antibodies are used to treat various human diseases, subsequent treatments with unrelated mouse antibodies may be ineffective or even dangerous in themselves, because of cross-reactivity.
Thus, there is a need for improved forms of humanized immunoglobulins specific for γ-IFN antigen that are substantially non-immunogenic in humans, yet easily and economically produced in a manner suitable for therapeutic formulation and other uses. The present invention fulfills these and other needs.